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Cannabis & Human Biology

As we begin to learn more about cannabis and its chemical compounds, chiefly cannabinoids, you might have heard of a complicated term in the middle of the cannabis discussion: Endocannabinoid System.

Before we jump into the specific science of the endocannabinoid system (ECS), think of it as a catchall term that describes the equalizer preset you were born with, like audio equalizers. Introducing THC to your ECS allows you to drive up or drive down signal amplification for each individual value, such as hunger, hearing, and proprioception, or your understanding of movement and spatial orientation. The munchies, for example, represent an amplified hunger signal.

The Endocannabinoid System

Every function in our bodies requires a specific balance of factors in order to perform at maximum capacity. When this balance is achieved, it’s called homeostasis. The endogenous cannabinoid, or endocannabinoid system (ECS), plays a major role in survival by helping to maintain homeostasis in fish, reptiles, birds, and mammals (including humans).

Pain, stress, appetite, energy metabolism, cardiovascular function, reward and motivation, reproduction, and sleep are just a few of the functions the endogenous cannabinoid system is involved in.

The ECS consists of three main components: “messenger” molecules that our bodies synthesize, the receptors these molecules bind to, and the enzymes that break them down. This system is present throughout the entire body — it’s on immune cells in our bloodstream, on our nerves throughout our extremities, on the entire axis of the spinal cord, and in virtually every cell in our entire brain. There are even cannabinoid receptors in our skin.

The body naturally produces two known cannabinoid molecules: anandamide and 2-arachidonoylglycerol (2-AG). Because anandamide was only discovered in the 1990s, there is still a great deal of research and study to be done in order to fully understand these endocannabinoid molecules.

Anandamide and 2-AG seek out cannabinoid receptors CB1 and CB2. While these two receptors have been the most studied by scientists, there are others. Anandamide and 2-AG also activate TRPV proteins. TRPV proteins are responsible for the body’s sensations of heat and cold. For example, that heat you experience when you eat chili peppers — that’s a TRPV response.

Although the CB and TRPV receptors are the major players in the ECS, there are at least three other receptors that may eventually be considered cannabinoid receptors, once their functions are fully understood (GPR55, GPR18, and GPR119).

CB1 receptors are largely found in the central nervous system, where they regulate a wide variety of brain functions. In fact, they’re the most widely expressed protein of their kind in the brain. In the brain, the major role of the CB1 receptor is to regulate the release of other neurotransmitters, such as serotonin, dopamine, and glutamate. Think of these neurotransmitters as children waiting to enter a crosswalk after school: The endocannabinoid system acts as the crossing guard, allowing them to cross at very tightly controlled times and amounts. Although the CB1 receptor is responsible for the euphoric effects of cannabis, it’s also critically involved in the brain’s top-down control of pain.

CB2 receptors are mostly found on immune cells, which circulate throughout the body and brain via the bloodstream. They’re also found on neurons in a few select brain regions. CB2 receptors are involved in pain relief, anti-inflammation and neuroprotection.

Anandamide and 2-AG are produced by our cells in an “on demand” fashion. They are commonly referred to as “retrograde messengers” because they float backwards across the gap between two neurons, in the opposite direction of normal neuronal communication. After binding to their targets, the endogenous cannabinoids are rapidly broken down by enzymes FAAH and MAG lipase. FAAH, or fatty acid amide hydrolase, breaks down fatty acid amides like anandamide, while MAG lipase, or monoacylglycerol lipase, breaks down 2-AG.

Several pharmaceutical companies have identified these enzymes as potential targets for new classes of drugs to treat pain. The rationale is that if the endocannabinoid molecules relieve pain, then perhaps increasing their presence (by preventing their enzymatic breakdown) would be a “natural” mechanism of pain relief. Unfortunately, this approach has proven to be much more dangerous than stimulating the endocannabinoid system directly, by introducing cannabinoids from the cannabis plant.

Because our bodies already use cannabinoid molecules to regulate many functions, we’re inherently endowed with many targets the cannabis plant can activate. Phytocannabinoids (plant-derived cannabinoids) are compounds that are unique to the cannabis plant, produced by trichomes on its surface. Beyond the known and potential cannabinoid receptors mentioned above, phytocannabinoids bind to many other targets. For instance, cannabidiol (CBD) has at least 12 sites of action in the brain.

Everyone’s endocannabinoid system is unique: the rates of 2-AG and anandamide production and break down can vary wildly, and so can the levels of cannabinoid receptors in our bodies. For instance, prolonged use of cannabis causes the brain to reduce the number of CB1 receptors that are available for activation. Using human brain imaging, we can observe that just 48 hours of abstinence from cannabis is sufficient to resensitize the system and bring the expression of CB1 proteins to a level that is comparable to a non-cannabis user.

Individual differences in this system also occur due to genetic variations (mutations) in both the receptors (CB1 and CB2) and the degradation enzymes (FAAH and MAG-lipase). In the future, it may be possible for doctors to screen for the presence of these genetic variations in a simple DNA test, so patients can have some idea of what their ECS looks like before starting cannabis therapy. This type of biological screening would be incredibly useful in finding the right kind of cannabis therapy for the right patient.

How Terpenes Work with Cannabinoids to Produce the Cannabis Plant’s Most Desired Effects

Some of the cannabis plant’s most appealing qualities are the aromas and flavors we experience when we consume it. Many of the most popular strains are named after their intended taste. Blueberry is named for its sweet, citrusy blueberry flavor, Sour Diesel for its pungent and intoxicating fuel-like aroma, and Cheese for its, well, cheesy taste and smell.

You can thank terpenes for all the cannabis flavors and aromas you love. Whether you smoke cannabis flower, dab concentrates, or vaporize either, terpenes are hard at work delivering tasty citrus, diesel, woody, pine, skunky, coffee, spicy, herbal, or tropical flavors to your palate.

But terpenes do more than provide flavor and aroma. They also support other cannabis molecules in producing wanted effects. We call this the entourage effect, and it’s the reason terpenes have become such a critical piece of the cannabis puzzle.

Cannabis contains hundreds of molecules that have the ability to directly interact with our bodies and minds. Cannabinoid molecules are relatively unique to the cannabis plant, but other plant-derived molecules such as flavonoids and terpenes also bind to our cells and influence our experiences.

Terpenes are a large class of molecules that are produced by many species of plants. They are the main ingredient in essential oils, and are the fragrant compounds responsible for plants’ distinctive smells. The cannabis plant produces at least three dozen different terpenes. The unique scent of each cannabis cultivar (strain) is a result of the unique balance of terpenes produced by that particular plant. Terpenes dissipate into the air very easily, and are the first molecules to vaporize when heat is applied to flower. The flavor of terpenes is maximized by whole-flower vaporization, which gives the brain a chance to interpret the flavor without overwhelming it with the taste of smoke.

In addition to their aromas, terpenes have direct interactions with our bodies. For instance, alpha-pinene and beta-caryophyllene interfere with molecules that dilate our blood vessels. Less dilation equals less inflammation. Evidence suggests that whole-plant cannabis (that includes terpenes) is superior to isolated compounds from the plant. This isn’t entirely surprising: if pinene is anti-inflammatory, and CBD is also anti-inflammatory, then the body has a chance to fight inflammation from two different angles, using a single flower. This combined benefit is known as the Entourage Effect; cannabinoids like THC and CBD produce better outcomes when they are consumed alongside a supporting cast of terpenes.

So how is this all happening? What bodily processes or mechanisms could explain why combined terpenes and cannabinoids are superior to isolated ones? Like the example above, one possibility is that cannabinoids and terpenes hit different targets, and the summed activity at those targets (receptors or other cellular pathways) results in a better outcome; in other words, attacking inflammation at multiple sources of inflammation. It’s also plausible that terpenes could enhance our bodies’ ability to absorb or process cannabinoids. On the other hand, we have decent evidence that the undesirable effects of cannabis are minimized when there is a diverse set of molecules consumed at once. For instance, when CBD is consumed alongside THC, people experience less paranoia and anxiety.

The thing about the word “entourage” is that it gives the connotation that all the work is being done by a prevalent cannabinoid (like THC or CBD), while the other minor cannabinoids and terpenes are there as a sea of relatively insignificant minions. In some cases this may be true, like when an individual uses an extremely THC dominant flower (20+ %) that doesn’t have much else going for it.

However, there are a staggering variety of chemical phenotypes (chemotypes of cannabis) out there in the world. Plants that have a rich diversity of cannabinoids and terpenes may fall more into an “Ensemble” effect, rather than an “Entourage.” Just like an orchestra, each individual instrument contributes to the overall experience of the musical piece. THC may be the conductor, and CBD might be first-chair violin, but every instrument, every different cannabinoid molecule, contributes to the overall experience.

Almost everything we know about terpenes and cannabinoids is a result of studying their properties in isolation. With the exceptions of THC and CBD, the majority of this work has been done in animal models and petri dishes. Although this kind of science tells us a lot about the cellular mechanisms by which cannabinoids promote health, these models could be a bit too simplistic to generalize the results to the entire human population.

In the real world, we usually don’t consume isolated alpha pinene and wait to see how much it improves our breathing. Isolated cannabinoids like CBN are becoming more common. But, just because they’re being more widely consumed doesn’t mean there is sufficient clinical research to fully understand how they function in the real world, alongside others. Most “evidence” is purely anecdotal at this point. It’s far more common (and more beneficial) for us to consume hundreds of molecules at a time. There is a huge amount of research left to do in order for us to understand exactly how terpenes enhance the other health benefits of the cannabis plant, and exactly which constellations of molecules produce the different kinds of highs for which cannabis is known.

Why THC Gets You High and CBD Doesn’t, Explained

Whether it’s THC and CBD, or tetrahydrocannabinol and cannabidiol, respectively, chances are you’ve heard about these two cannabinoids. They’re not only the most well-known, but the most prevalent compounds in the cannabis plant.

The quick wrap on these two compounds usually goes something like this: THC gets you high and CBD doesn’t, but that’s just a small part of the story.

Each cannabis plant contains a rich profile of cannabinoids that interact with our bodies in unique and sophisticated ways. Start unpacking the science behind THC and CBD, and one thing becomes clear: there’s far more to these incredible cannabinoids than their most apparent effects would suggest.

THC is Cannabis’ Most Well-known and Desired Compound

Cannabis is one of the safest intoxicating substances on the planet. As with other intoxicating drugs, the precise mechanisms by which cannabis produces intoxication aren’t entirely known. We can, however, conclude a few important things.

The main intoxicating ingredient in cannabis is delta-9-tetrahydrocannabinol (THC). The intoxicating properties of THC were first described in the 1940s, however our understanding of THC dramatically improved once the Israeli scientist Rafael Mechoulam synthesized this molecule in 1965.

THC is an agonist, or activator, of the cannabinoid 1 (CB1) receptor. When cannabis is given to people who have had their CB1 receptors blocked (by a different drug, called an antagonist), cannabis cannot get them high. So, we know that the CB1 receptor must be the critical target in the brain that produces intoxication.

Brain imaging studies have shown increased blood flow to the prefrontal cortex region of the brain during THC intoxication. This region of the brain is responsible for decision-making, attention, and other executive functions, like motor skills. In short, THC intoxication can affect any of these functions to varying degrees depending on the person.

Another important factor in cannabis intoxication involves the activation of the brain’s reward circuitry, which feeds our emotional and memory processes. Ultimately, the activity in these regions produces pleasurable sensations and emotions that encourage us to revisit that greasy burger place for a calorie-dense meal or ask a potential mate out on another date.

Cannabis activates the brain’s reward pathway, which makes us feel good, and increases our likelihood of partaking again in the future. THC binding to CB1 receptors in the brain’s reward system is a major factor in cannabis’ ability to produce feelings of euphoria.

There is a Lot More to CBD Than “It Doesn’t Get You High.”

But THC is far from the only ingredient in cannabis that has a direct impact on brain function. The most notable comparison is with cannabidiol (CBD), which is the second most abundant cannabinoid found in the plant. CBD is often touted as “non-psychoactive,” however this statement is somewhat misleading. Any substance that has a direct effect on the function of the brain is considered to be psychoactive. CBD most certainly does this, as it has very powerful anti-seizure and anti-anxiety properties.

CBD is indeed psychoactive; it’s just not intoxicating. The reason for this is that unlike THC, CBD is exceedingly bad at activating the CB1 receptor. In fact, evidence suggests that it actually interferes with the activity of the CB1 receptor, especially in the presence of THC. When THC and CBD work together to affect CB1 receptor activity, users tend to feel a more mellow, nuanced subjective high and have a much lower chance of experiencing paranoia compared to the effects felt when CBD is absent. That’s because THC activates the CB1 receptor, while CBD inhibits it. The presence of both cannabinoids balances the effects.

Things get particularly interesting when other cannabinoid and terpene molecules are consumed alongside THC and CBD. Although we are just beginning to understand the isolated effects of cannabinoids such as CBN, CBC, and CBG, their ability to bind to targets in the brain means they could potentially enhance, interfere with, prolong, or in some other way modulate the effects of THC. It’s entirely possible that some of cannabis’ most well-known effects (such as couch lock) may have very little to do with THC itself, but rather, the relative contributions of these lesser-known molecules.

Cannabis is a complex plant with relatively little available research into its effects and interactions with the human body — and we’re just beginning to learn the many ways cannabis compounds work together to change the way we feel.

Why Do Different Cannabis Varieties Give You Different Kinds of Highs?

Those mushroom-shaped structures are known as trichomes, and packed inside each and every one of them is a diverse array of biologically active molecules. More than 100 unique cannabinoid molecules have been identified so far, and any given cannabis plant can produce dozens of them in different ratios.

Every cannabinoid is structurally different than the rest. Even a subtle shift in the chemical bonds within a molecule can dramatically change its 3-dimensional shape. It’s the unique shape of the molecules within the cannabis plant that very strictly dictates exactly how they interact with our bodies. Delta-9-THC for instance, interacts directly with the CB1 receptors in our brain to produce euphoria and intoxication. CBD, despite being capable of more than a dozen types of actions, does not produce euphoria because its 3-dimensional shape doesn’t allow it to activate CB1 receptors. The saying “you can’t fit a square peg into a round hole” literally applies here.

Cannabinoids aren’t the end of the story, though. Like countless plants on planet Earth, cannabis also produces aromatic, or fragrant molecules known as terpenes. Terpenes give plants their signature smells (such as pinene, found in conifer trees, and limonene, found in citrus plants). In addition to being fragrant, terpenes also directly interact with the cells in our brains as a result of their unique chemical composition and 3-dimensional shape.

Speaking of shape, let’s talk about Indica and Sativa for a moment. In the late 1700s, botanists gave these names to different kinds of cannabis plants scattered across the globe. These different names were assigned due to differences in how the plants looked. At that time in history, the morphologically and genetically distinct plants across the globe probably produced very distinct effects in people as well. Sativa plants may very well have been uplifting, and Indica plants may have been sedating.

A lot has happened in 200 years, however. The subjective high is certainly not driven by the shape of a plant, and even its genetic lineage says little about what kind of high it will produce: it all comes down to the molecules. The many and varied types of cannabis intoxication are solely a result of which molecules were consumed, in which ratios, and at what dose. Scores of molecules competing for binding sites, synergizing with one another, interfering with one another, supporting and modulating one another — that’s the difference between energized and couch locked, not Indica and Sativa.

Despite an incredible amount of effort on the behalf of cannabis cultivators, no two cannabis plants ever produce identical levels of cannabinoids and terpenes. Even two genetically identical clones of the same mother plant can have meaningful variability in their chemistry. The plant’s genes, the growing instructions embedded in the DNA, generally guide which molecules the plant will produce. The amount or relative expression of those molecules, however, is very sensitive to growing, harvesting, and curing conditions.

So how do we know what kind of high we’ll experience when we buy a particular flower?

In short, we don’t. The best we can possibly do at the moment is pay attention to the kind of experience a particular cannabinoid and terpene ratio produced and look for a similar makeup, rather than keeping track of what a particular strain did for us.

Ever Smoke the Same Flower with a Friend Only to Have Completely Different Experiences? Your Genes might have a lot to do with it

So, you’re at a friend’s house, and they hand you a joint. “Be careful,” your friend warns. “This flower is really strong.” You take a drag and next thing you know, you’re feeling … absolutely nothing.

Sound familiar? It illustrates a pretty common occurrence — the same toke exhibiting different effects in different folks — one for which we might have no one to blame but ourselves. Or, more accurately, our own genes.

Cannabis is able to produce a wide array of experiences in human beings. It can make us sleepy, enhance our relationships, change our perception of the world and relieve the symptoms of debilitating diseases. And while different kinds of cannabis products produce different effects, what is even more interesting is that the same cannabis product can produce very different effects among individuals.

For instance, in passing a joint amongst a group of friends, some people may be completely unaffected while others experience intense intoxication of one variety or another. Why is that?

Cannabis exerts its effects through many targets and mechanisms within the brain, most notably the CB1 and CB2 receptors. These receptors are proteins that are made inside of our cells, and like all other proteins our bodies make, the “blueprints” for how to build them reside in our DNA. Although the human genome (the collection of all human genes) is strikingly similar across people, random or inherited edits (mutations) in these blueprints are extremely common. Genetic mutations can often be the source of inherited diseases, and they can also account for some of the differences in people’s reaction to cannabis.

Mutations in the human CB1 receptor (the target for THC and main site of cannabis intoxication) were first observed more than a decade ago. So far, scientists have identified nine variations of this gene in humans. When the blueprints for the protein are different, the function of the protein is almost always affected.

This means that right now, you’re walking around with one of at least nine different versions of the CB1 receptor protein. In some cases, a CB1 mutation could make you more vulnerable to diseases like anorexia, Crohn’s, or addiction, but in others it could drastically alter your sensitivity to the molecules that bind to it (like THC). This could very well explain why an individual’s sensitivity to cannabis intoxication could be greater or less than the eight other friends sharing the joint.

There are also at least seven mutations in the human FAAH gene (an enzyme that breaks down our bodies’ naturally produced cannabinoid molecules), and four mutations in the CB2 receptor. These mutations could have major health implications, and are the subject of intense ongoing research.

But genetic mutations affected by cannabis aren’t restricted to the genes involved in our endogenous cannabinoid system. For example, some people have mutations in the Akt gene (Protein kinase B, not an endocannabinoid-specific gene). This gene can keep cells from dying and inhibit tissue growth and is associated with many types of cancer. People with this mutation are more prone to make errors in judgement and motor responses after consuming cannabis. That’s because the individual’s Akt mutation changes how cannabinoids affect them.

Another important variation outside of the endocannabinoid system is found in the liver. When cannabis is ingested orally (swallowed tincture or edibles), it passes through the digestive system and liver before the cannabinoids can get into the bloodstream and brain. The liver contains many enzymes (again, proteins encoded by our DNA) that process many kinds of medications and substances. One of the more notable enzymes in the liver converts delta-9-THC into 11-hydroxy-THC, which is even more potent at activating the CB1 receptor and inducing intoxication. There are virtually countless individual differences in the efficiency and diversity of liver functions that could affect our experience with edible cannabis.

The genetic mutations that change our experience of cannabis may be present from birth, but they can also occur as a result of our experiences. Genes get turned off and turned on almost constantly throughout our daily lives, in response to many stimuli (invading viruses, diet, stress, you name it). At some point in the near future, it might be possible to do a simple DNA test (swabbing the inside of your cheek) to determine what your genes look like, and what you might be able to expect from using cannabis.

How Cannabinoids Are Converted, the Deal With Eating Raw Cannabis, and What That Little “A” Actually Means, Answered.

You may have stumbled upon an interesting ingredient in the search for a super healthy juice or smoothie recipe: raw cannabis.

And no, that isn’t a mistake. Raw cannabis belongs to the realm of superfoods alongside avocados, kale, and greek yogurt; they help fight arthritis, chronic pain, and other maladies — without any intoxicating effects.

This is all thanks to Tetrahydrocannabinolic Acid (THCA), a cannabinoid that, until recently, has been most closely related to Tetrahydrocannabinol (THC), the most intoxicating chemical compound in cannabis. The relation? THCA becomes THC.

Which begs the question: how is THCA non-intoxicating when consumed in raw cannabis (fresh, uncured, and unheated) but intoxicating once it has become THC?

Decarboxylation: How Cannabinoids Convert to Change the Way They Interact with Our Bodies.

The cannabis plant produces hundreds of cannabinoids, the chemical compounds responsible for the therapeutic and psychoactive effects of cannabis. But only a few cannabinoids cause the euphoric high that is unique to the cannabis plant. Most people assume that during the growth period the cannabis plant is producing THC, the most desired cannabinoid to cannabis cultivators, when it is actually primarily producing a larger molecule: THCA.

THCA is the non-intoxicating precursor that becomes THC when exposed to heat over a prolonged period of time. THCA that’s found in the cannabis plant won’t make you feel high. This is how you can eat or drink the raw plant and not feel its intoxicating effects.

But what keeps THCA from producing the intoxicating effects of THC? The simple answer: The THCA molecule doesn’t fit into the brain’s cannabinoid receptors.

In terms of physical size, THCA is a larger compound than THC. This is due to the extra carboxyl group attached to the molecule; it’s this carboxyl group that defines THCA as an acid. In fact, most cannabinoids (CBDA, CBGA, THCVA) take this acidic form when harvested and it is only later that they become the cannabinoids (CBD, CBG, THCV) we’re more familiar with.

The term for converting THCA into THC is decarboxylation. Simply put, it’s the process of removing the carboxylic acid group from a cannabinoid, a change that enhances its ability to interact with the body. Without decarboxylation, THCA have very little affinity for the cannabinoid type I (CBI) receptor since they can’t fit. CB1 receptor activation is a requirement for intoxication; if molecules don’t fit here, they can’t get you high.

Heat removes a carboxylic acid group from THCA, and the molecule decarboxylates into THC. As a smaller cannabinoid, THC is able to bind to CB1 receptors throughout the human body, producing intoxication.

Heat, Light, and the Many Ways THCA Converts to THC.

THCA is considered “thermally unstable,” which is another way to emphasize that it will alter when provoked by heat. Because of THCA’s instability, the molecule lends itself to several different methods of decarboxylation.

Sunlight conversion: THCA can convert to THC to varying degrees through exposure to light and heat. If a cannabis plant sits in the warm sun for an extended period of time, its THCA compounds will slowly convert to THC.

Room temperature conversion: THCA also converts to THC when stored at room temperature for a long enough time. In an olive oil extract, 22% of THCA will convert to THC over the course of 10 days at 77 degrees. Under the same conditions, 67% of THCA in an ethanol extraction will convert. Over time, cannabis stored at room temperature with very little light exposure will convert 20% of its THCA to THC.

Smoking: If dried and cured bud is exposed to a high degree of heat for a short time, as a match or lighter would provide during smoking, much of the existing THCA rapidly changes to THC. However, not all THCA converts to THC (smoking isn’t the most efficient method of decarboxylation).

The Benefits of THCA and Reasons to Go Raw

The raw cannabis movement is largely led by the benefits of THCA. More consumers are looking for smoothie and juice recipes to consume raw cannabis for its non-intoxicating, medicinal benefits (thanks to CBD’s rise in popularity).

Research is still preliminary and some results are still anecdotal, but the consumption of cannabinoid acids (the “A” in THCA) is believed to be a key to preventing chronic diseases (IBS, glaucoma, fibromyalgia) caused by an endocannabinoid production deficiency.

THCA is commonly being used as a nutritional supplement and dietary enhancer for its:

Anti-inflammatory properties to help with conditions like lupus and arthritis

Antidiabetic properties, reducing the risk of developing early onset diabetes

Neuroprotective properties to treat neurodegenerative diseases

Antiemetic properties to battle loss of appetite and nausea

Whether you’re smoking or juicing, understanding the various ways cannabinoids convert and interact with our bodies is crucial to achieving the effects we desire (and avoiding the ones we don’t). As more research is conducted in pursuit of a deeper understanding of how humans and cannabinoids interact, we can safely integrate raw cannabis into our daily diets to take full advantage of everything the plant has to offer.